Phenthiazine derivatives



nit d mm 7 2,891,952 PHENTHIAZINE DERIVATIVES Paul Gailliot, Paris, Je'an Robert, Gentilly, and Jacques Gaudechon, Thiais, France, assignors to Societe des Usines Chimiques Rhone-Poulenc, Paris, France, a French body corporate No Drawing. Application July 11, 1957 7 Serial No. 671,136

Claims priority, application France July 19, 1956 6 Claims. (Cl. 260-243) g This invention relates to new derivatives of phenthi azirie and to processes for'their production. L. 1 It is known that various IO-aminoalkyl-phenthiazines possess interesting therapeutic properties. Extensive research and experimentation has shown, however, that both the size of the therapeutic index and the nature of the therapeutic efiect exhibited by certain compounds of this type can radically be changed (even 'e1iminated)..by even-small changes in chemical structure. is this the case with variations in the nature and length of the side chain attached to the IO-position nitrogen atom and with positional substitution in the phenthiazine nucleus.

It is an object of the present invention to provide new phenthiazineden'vatives which possess useful pharmacological properties. It is a further object of the invention to provide processes for the production of these new compounds.

The phenthiazine derivatives of the present invention are those which conform to the formula:

and their salts and theirquaternary ammonium derivatives (wherein R represents a hydrogen atom oranalkyl group, R represents an alkyl group, R and R are the same or difierent and either each represents a lower alkyl group or one of R and R represents a hydrogen atom and the other represents a lower alkyl group or R and R together with the adjacent nitrogen atom collec- Particularly thiazines. The majority of methods so applied can be described generically as consisting in reacting a phenthiazine derivative of general formula:

with a compound Q, the groups P and Q being such that Q will react with the phenthiazine derivative soas to introduce the substituent or a substituent easily convertible into forming the convertible substituent into tively represent a heterocyclic group such as pyrrolidino,

piperidino, morpholino, piperazino, 4-alkylpiperazino, 4- hydroxyalkylpiperazino or 4-acyloxyalkylpiperazino, and B represents a straight or branched chain divalent aliphatic hydrocarbon group containing two to four carbon atoms. (such, for example, as ethylene, propylene, isobutylene, trimethylene or tetramethylene) unsubstituted or substituted by a group wherein A represents a single bond or a methylene group and R and R are as hereinbefore defined.

-:The terms alkyl andacyl as used in this specificationiand 'in the appended claims embrace solely alkyl.

1 Preferred processes of manufacture are as follows;

(1) Alkylation of a 3-hydroxyalkylphenthiazine corresponding to general Formula I in whichR represents a hydrogen atom and the other groups are as hereinbefore defined. The reaction is advantageously carried out by conversion of the hydroxy group into a more re-' active substituent such as a halogen atom and conden sationot the halogen derivative thus obtained with a metal alcoholate or with an alcohol in the presence of an alkali metal hydroxide. When the grouping i represents a 4-hydroxyalkylpiperazinyl group this group may conveniently be protected by for example tetrahydropyranylation.

(2) Interaction of a 3-alkoxyalkylphenthiazine of the general formula:

E ORa 111 (wherein R and R are as hereinbefore defined) with a halogenamine of the formula:

hydrocarbon solvent medium (for example, benzene,v

toluene or xylene) in the presence of a condensing agent, preferably in the form of an alkali metal or derivative thereof'(such as, for example, hydride, amide, hydroxide, alcoholate or metal alkyl or aryl) and especially in the .form of metallic sodium, sodamide, powdered sodium or potassium hydroxide, lithium hydride, sodium 5 tert-hutylate, butyllithium or phenyllithium. The reaction is preferably carried out at the boiling temperature of the solvent. It is advantageous to use the halogenoamine in the form of the free base in solution, for example, in benzene, toluene or xylene, and to add this to'the mixture of the other reactants in which the phenthiazine reactant of Formula III may already be present, at least in part, in the form of an alkali metal salt. The reaction may also be carried out using a salt of the halogenoamine but in this case a greater proportion of the condensing agent must clearly be used in order to neutralize the acid of the salt employed.

In the case where the divalent aliphatic hydrocarbon group .--B is an asymmetric branched chain, such for example (3) Decomposition of an aminoalkylphenthiazine--- carboxylate of the formula:

(where the various symbols are as hereinbefore defined) by heating the carboxylate to a temperature above 100 C., and preferably between 150 and 220 C. There is no advantage in operating at higher temperatures which can often cause strong coloration of the reaction products.

The reaction can be effected with the phenthiazine- 10-carboxylate alone, i.e. without a diluent, or in an inert medium such as o-dichlorobenzene, diphenyl or diphenyl oxide, or in the classical diluents for decarboxylation, such, for example, as quinoline or weak bases of high boiling point.

During the course of the decomposition of the phenthiazine-lO-carboxylate an isomerisation, similar to that hereinbefore described in process (2), takes place when the divalent aliphatic hydrocarbon group B is an asymmetric branched chain.

The phenthiazine-lO-carboxylates employed as starting materials may be obtained by known methods. For example, they may be prepared by the action of a halide (or an ester) of the corresponding phenthiazine-lO-t carboxylic acid on the appropriate aminoalcohol; or by the action of a halogenoalkyl ester of such an acid on the appropriate secondary amine.

4 (4) Interaction of an amine of the formula R4 (wherein R and R are as hereinbefore defined) and a reactive ester of the-general formula:

(wherein R and R are as hereinbefore defined, Y rep resents a residue of a reactive ester such as a halogen atom or a sulphonic ester residue and B represents a straight or branched divalent aliphatic hydrocarbon group containing two to four carbon atoms or such a grouping'substitute'd by'a group -AY' A being as hereinbefore defined and Y being a residue of a reactive ester or a grouping (5) Alkylation by known methods of the correspond ing-primary or secondary amines, i.e. those compounds of Formula I in which the grouping(s) represents groups such as" amino, monoal'kylamino or piperazino, leading to the production of compounds in which the grouping(s') represents such groups as monoalkylamino, dialkylamino, 4-alkylpiperazino, 4-hydroxyalkylpiperazino or 4-acyloxyalkylpiperazino.

(6) Cyclisation, preferably in a solvent in the form of a substituted amide of a lower aliphatic acid such as formamide or acetamide, or in dimethylaniline, in the presence of a condensing agent (alkali metal hydroxide or carbonate) and optionally in the presence of a catalyst such as copper powder, of aderivativeof general formula:

NH Hal are 4-hyrlroayalkylpip erazino groups.

VIL.

the'compounds conforming to general Formula I have an asymmetric carbon atom in the chain B, such as those compounds with the branched chain Jill.

and consequently can exist in optically active forms. The invention includes within its scopethe racemates as well as the correspondingly optically active isomers of such compounds. The optically active isomers may be obtained by e.g. methods (2) and.(4) described above by commencing with starting materials which are themselves optically active. They may also be prepared by optical resolution of the corresponding racemates.

vThe products prepared according to the invention have valuable pharmacodynamic properties. They have, in particular, a powerful action on the central nervous sys- 0 tern,- renders, them generally useful as neuroleptics, as' potentiators of general anaesthetics (for example, hexobarbitone and, ether) and analgesics (for example, morphine), and as anti-emetics. Certain of them .are also ,spasmolyticsand antihistaminics. I

Compounds of the invention which are outstanding in their action onthe central nervous system are those in which'the group B is of the form CH --CH CH or, 1 v

I. v) I I -CHf-GBF-CHzthe grouping 4 represents dimethylamino, diethylamino, 4-methylpiperazino, 4-hydroxyethylpiperazino or 4-acetoxyethylpiperazino and R and R are as hereinbefore defined. Compounds of the invention in which the grouping B N R4 represents -CH3CH-N(CH;)1

a or '0H,-cHoH,-N oH3 H: are powerful antihistaminics.

Finally, those in which the group Rt contains a group in particular those in which the group represents a bis-(dia1kylamino)propyl group, and more particularly a 2:3-bis-(dimethylamino)propyl group, are especially useful as spasmolytics, as may be shown experimentally by their antagonistic action against spasm of the isolated rabbit intestine provoked by acetyl choline or barium chloride.

For therapeutic purposes, the bases of general Formula I are preferably employed in the form of acid 76 lit/mitt [11mm tilrttt lllflllfil, (ll/illitt mall.

anesulphon-ates and ethanedisulphonates) or of quaternary ammonium salts obtained by reaction with organic halides (e.g. methyl or ethyl iodide, chloride or bromide or allyl or benzyl chloride or bromide) or other reactive esters conveying pharmaceutically acceptable anions.

The following examples show how the invention may be put into practice. Unless otherwise indicated the melting points stated were determined on the Kofler bench.

, Example I A solution of 3-(1-chlorethyl)-10-(3-dimethylaminopropyl)phenthiazine hydrochloride (2 gL) in methanol (20 cc.) is added over a period of 15 minutes at ordi-' nary temperature to a solution of potassium (0.84 'g.)'

inmethanol (10 cc.). r

The solution is then heated for 17 hours under reflux with stirring. After cooling, the methanol is distilled oflf in vacuo and the residue taken up with water (50 cc.) and ether (50 cc.). After vigorous shaking, t he ethereal layer is decanted, washed with water (10 cc.) and dried over sodium sulphate and the ether is distilled off on the water-bath.

The crude oily base obtained is purified by conversion to the oxalate in acetone. 3-(l-methoxyethyl)-10-(3- dimethylaminopropyl)phenthiazine oxalate (1.85 g.), M.P. 193l94 C. (Maquenne block), is thus obtained.

3 (1 chloroethyl) 10 (3 dimethylaminopropyl)- phenthiazine hydrochloride, M.P. l73-l74 C. (Maquenne block), which serves as the starting material for the preceding product, is obtained by the action of thionylchloride in chloroform on 3-(l-hydroxyethyl)-l0-(3-' dimethylaminopropyl)phenthiazine; the hydrochloride formed is precipitated from the chloroform solution by the addition of anhydrous ether. p v 1 Example 11 The following mixture is heated for 20 hours under reflux:

3 (1 chloroethyl) 10 (3 dimethylaminopro- After cooling, the ethanol is distilled in vacuo and the residue is treated with water cc.) and ether (100 cc.). The ethereal layer is decanted and extracted with N hydrochloric acid (100 cc.). The hydrochloric acid extract is made alkaline with sodium hydroxide (d=1.33, 15 cc.) and the oily base which precipitates is extracted with ether (100 cc. followed by 50 cc.). The combined ethereal extracts are washed with water (2 x 20 cc.) and dried over anhydrous sodium sulphate. After distillation of the ether on the water-bath the crude base is purified by conversion into the oxalate in acetone. After recrystallisation from ethanol, there is obtained 3 (1 ethoxyethyl) 10 (3 dimethylaminopropyD- phenthiazine oxalate (2.8 g.), M.P. 165-166 C. (Maquenne).

Example III A solution of 3-methoxymethylphenthiazine (12.15 g.) in anhydrous xylene cc.) is heated under reflux and treated with sodamide (2.4 g.). A solution of 1-dimethylamino-3-chloropropane (7.3 g.) in anhydrous xylene (30 cc.) is then added over 40 minutes. The mixture is heated under reflux for 3 hours, cooled and is then treated with water (100 cc.) and hydrochloric acid (d=1.19, 12 cc.). The xylene phase is separated and the aqueous phase is made alkaline with sodium hydroxide (d=l.33, 16 cc.). The liberated base is extracted with ether (2. x 100 cc.), the ethereal extracts Proceeding as in Example 111 but commencing with 3-methoxymethylphenthiazine (12.15 g.) and l-methyl- 4-(3-chloropropyl)piperazine (10.6 g.), there is obtained 3 methoxymethyl 1O (3 4' methyl 1' piperazinylpropyl)phenthiazine (14.7 g.), B.P. 248252 C./0.6 mm. Hg, whose di-hydrochloride melts at 192-194 C.

Example V Proceeding as in Example III but commencing with 3-methoxymethylphenthiazine (12.15 g.) and 1dirnethylamino-Z-methyl-3-chloropr0pane (8.15 g.), there is obtained 3 methoxymethyl 10 (3 dimethylamino 2- rnethyl-propyl)phenthiazine (13.6 g.), B.P. 202209 C./ 0.5 mm. Hg, whose acid oxalate melts at 124 C.

Example VI Proceeding as in Example III but commencing with 3 rnethoxymethylphenthiazine (20.9 g.) and 1:3-bis-(dimethylarnino)-2-chloropropane (16.95 g.), there is obtained 3 methoxymethyl 1O [2:3 bis (dimethyl amino)propyllphenthiazine (31.6 g.), B.P. 210-218 CL/L3 mm. Hg, whose acid oxalate melts at 199 C. and acid maleate at 113 C.

Example VII Proceeding as in Example III but commencing with 3-ethoxymethylphenthiazine (12.85 g.) and l-dimethylamino 3 chloropropane (7.3 g.), there is obtained 3 ethoxymethyl (3 dimethylaminopropyl)phenthiazine (14.8 g.), B.P. 205211 C./0.9 mm. Hg, whose acid oxalate melts at 139 C.

The 3-ethoxymethylphenthiazineused, M.P. 120 C., isobtainedby the action of ethyl iodide upon the sodium derivative ofv 3-hydroxymethylphenthiazine in anhydrous xylene.

Example VIII A solution of 3-diethyla1ninopropyl 3-methoxyrnethylphenthiazinyl-lO-carboxylate (6 g.), prepared by the action of S-diethylamino-l-propanol upon 3-methoxymethylplienthiazine-10-carbonylchloride, in o-dichlorobenzene (30 cc.) is heated under reflux for 2 hours. After cooling the solution is extracted with N hydrochloric acid (2 x 30 cc.).

The base is liberated from the aqueous hydrochloric acid solution with sodium hydroxide (d 1.33) and extracted With ether (2 x 30 cc.). The extracts are dried over anhydrous sodium sulphate and the solvent is removed by distillation in vacuo.

There is obtained 3-methoxymethyl-1OPB-diethylamiuopropyDphenthiazine (2.6 g.;) vwhoseacid. oxalate meltsat Example IX A solution of 3-(3-methoxymethyl-l0-phenthiazinyl)- propyl toluene-p-sulp-honate (8.7 g.) and 1-(2-hydroxy-'=' ethyl)piperazine (7.4 g.) in anhydrous toluene (120 cc.) is heated under reflux for 3 hours. After cooling the mixture is washed with distilled water cc. followed. by 2 x 50 cc.) and the toluene layer is extracted with 05 N hydrochloric acid (100 cc.).

The base is liberated from the aqueous hydrochloric acid solution with sodium hydroxide (d=1.33, 7.3 cc.) and extracted with chloroform (2 x 25 cc.). The extracts are dried over anhydrous sodium sulphate and the chloroform is removed by distillation in vacuo. There is obtained l0-(3-4'-hydroxyethyl-1'-piperazinylpropyl)' 3-methoxymethyl-phenthiazine (6.75 g.) whose acid'dimaleate melts at 172 C.

We claim:

1. 3 (1 methoxyethyl) 10 (3 dimethylaminopropyl phenthiazine.

2. 3-methoxymethyl-10-(3-dimethylamin0propyl)plienthiazine.

3. 3 methoxymethyl 10 (3 4' methyl 1' piperazinylpropyl phenthiazine.

4. 3 methoxymethyl 10 (3 dimethylamino- 2 methylpropyl)phenthiazine.

5. 3 methoxymethyl 10 (3 4' hydroxyethyl l piperazinylpropyl phenthiazine.

6. A phenthiazine derivative selected from the class consisting of compounds of the general formula:

CH5-(]7HCHa-A wherein R is selected from the class consisting of hydrogen atoms and methyl groups, R is selected from the class consisting of methyl groups and ethyl groups, R

is selected from the class consisting of hydrogen atoms" and methyl groups and A is selected from the class consisting of dimethylamino, 4-methylpiperazino and 4-hydroxyethylpiperazino groups, and acid addition salts thereof having pharmaceutically acceptable anions.

References Cited in the file of this patent UNITED STATES PATENTS 2,534,237 Cusic Dec. 19, 1950 2,645,640 Charpentier July 14, 1953 2,789,978 Rath Apr. 23, 1957 OTHER REFERENCES Burger et al.: J. Org. Chem., vol. 19, No. 2, p. 1842 (1954). 

1.
 3. - (1 - METHOXYETHYL) - 10 - (3 - DIMETHYLAMINOPROPYL)PHENTHIAZINE.
 6. A PHENTHIAZINE DERIVATIVE SELECTED FROM THE CLASS CONSISTING OF COMPOUNDS OF THE GENERAL FORMULA: 